Projection of CSF3R+S100A8+S100A9+ BALF neutrophils onto our reference revealed (1) 1.5 fold change (FC) expansion of IFNactive neutrophils in severe COVID-19 relative to moderate disease (77% versus 52%; Extended Data Fig. 7a,b); (2) preferential activation of IFN-stimulated genes (ISGs), such as IFITM1, IFITM2, IFI6, IRF7 and ISG20, in severe COVID-19 neutrophils (Extended Data Fig. 7c); and (3) 4.7 FC higher IFNactive neutrophils in COVID-19 relative to bacterial pneumonia (14% versus 3%; Extended Data Fig. 7d–f). Here, S100A8 is linked to COVID-19.